H2S protects lipopolysaccharide-induced inflammation by blocking NFκB transactivation in endothelial cells

Bourque, Caitlyn; Zhang, Yanjie; Fu, Ming; Racine, Mélanie; Greasley, Adam; Pei, Yanxi; Wu, Lingyun; Wang, Rui; Yang, Guangdong

doi:10.1016/j.taap.2017.11.004

Cited by 43 publications

(24 citation statements)

References 45 publications

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“…We further revealed that this increased in ammation was mediated through the downregulation of H 2 S, as restoring H 2 S levels using NaHS or SAMe attenuated the upregulation of pro-in ammatory cytokines induced by high glucose. These results are consistent with previous ndings that H 2 S attenuates LPS-induced in ammatory response in endothelial cells and microglia [23,38]. Our previous preclinical research has also proved that H 2 S attenuates hippocampal in ammation in the AlCl 3 -induced mouse model of Alzheimer's disease [14].…”

Section: Discussionsupporting

confidence: 93%

“…Activation of mTOR modulated its downstream ubiquitous transcriptional factor NF-κB to facilitate the production of pro-in ammatory cytokines [21,22]. H 2 S plays an inhibitory role in lipopolysaccharide (LPS)-triggered in ammatory response via blocking the transactivation of NF-κB in endothelial cells [23]. Collectively, we predicted that H 2 S might modulate in ammation in neuronal cells by inhibiting the activated SIRT1/mTOR/NF-κB signaling pathway.…”

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confidence: 93%

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Hydrogen Sulfide Ameliorates High Glucose-induced Inflammation Through SIRT1-mTOR/NF-κB Signaling Pathway in HT-22 cells

et al. 2020

Preprint

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Background: Hyperglycemia-induced neuroinflammation promotes the progression of diabetic encephalopathy (DE). Hydrogen sulfide (H2S) exerts anti-inflammatory and neuroprotective activities against neurodegenerative diseases. However, its role in hyperglycemia-induced neuronal inflammation has not been investigated. Herein, we examined the effects and its related signaling pathway of H2S on inflammatory response in high glucose-treated HT-22 cells.Methods: A hippocampal neuronal cell line, HT-22, was used as an in vitro model to explore the function of H2S on inflammatory response triggered by high glucose. A dicyanoisophorone-based near-infrared fluorescent probe (NIR-NP) was synthesized to detect H2S levels in HT-22 cells. Western blotting, immunofluorescence and real time-qPCR were carried out to study the mechanism of action for H2S.Results: We found that high glucose (85 mM) decreased the level of endogenous H2S and the expression of cystathionine-β-synthase (CBS) which is the main enzyme for H2S production in the brain. Sodium hydrosulfide (NaHS, a H2S donor) or S-adenosylmethionine (SAMe, an allosteric activator of CBS) administration restored high glucose-induced downregulation of CBS and H2S levels. Importantly, high glucose upregulated the level of pro-inflammatory factors (IL-1β, IL-6, TNF-α) in HT-22 cells. Treatment with NaHS or SAMe alleviated this enhanced transcription of these pro-inflammatory factors, suggesting that H2S might ameliorate high glucose-induced inflammation in HT-22 cells. We also found that high glucose reduced SIRT1 protein levels. SIRT1 reduction elevated the level of p-mTOR, p-NF-κB and pro-inflammatory factors, which were restored by resveratrol (a SIRT1 agonist). These results suggested that SIRT1 might be an upstream mediator of mTOR/NF-κB signaling pathway. Furthermore, NaHS or SAMe treatment reversed the expression of SIRT1, mTOR and NF-κB under high glucose conditions.Conclusions: Our study revealed that high glucose decreased CBS to reduce the production of H2S, which in turn decreased the expression of SIRT1. The reduction of SIRT1 activated mTOR/NF-κB signaling to promote inflammation. Given that promoting H2S production using NaHS or SAMe can reverse high glucose-induced inflammatory response, our study might shed light on the prophylactic treatment of DE.

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Section: Discussionsupporting

confidence: 93%

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confidence: 93%

Hydrogen Sulfide Ameliorates High Glucose-induced Inflammation Through SIRT1-mTOR/NF-κB Signaling Pathway in HT-22 cells

et al. 2020

Preprint

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“…Other studies have shown that the activation of TLR4 by LPS increases the biosynthesis of CSE and H 2 S in mouse macrophages through p38/MAPKs and NF‐κB signaling . On the contrary, LPS decreased CSE expression in human endothelial cells and blocked H 2 S production in mouse aorta tissues . All these findings indicate that the activation of TLR4 by LPS may modulate the synthesis of H 2 S through the enzyme CSE.…”

Section: Discussionmentioning

confidence: 81%

“…33 On the contrary, LPS decreased CSE expression in human endothelial cells and blocked H 2 S production in mouse aorta tissues. 34 All these findings indicate that the activation of TLR4 by LPS may modulate the synthesis of H 2 S through the enzyme CSE. However, while a list of evidence of cellular regulation of H 2 S enzymes has been studied in other systems, the cellular source of the gene regulation could not be identified in the current study.…”

Section: Previous Studies Have Shown Interactions Between H 2 S and Tlr4mentioning

confidence: 93%

TLR2 and TLR4 interact with sulfide system in the modulation of mouse colonic motility

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Abecia

Peña‐Cearra

et al. 2019

Neurogastroenterology Motil

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Background H2S is a neuromodulator that may inhibit intestinal motility. H2S production in colon is yielded by cystathionine β‐synthase (CBS) and cystathionine γ‐lyase (CSE) enzymes and sulfate‐reducing bacteria (SRB). Toll‐like receptors (TLRs) recognize intestinal microbiota. The aim of this work was to evaluate the influence of TLR2 and TLR4 on the endogenous and SRB‐mediated synthesis of H2S and its consequences on the colonic motility of mouse. Methods Muscle contractility studies were performed in colon from WT, Tlr2‐/‐, and Tlr4‐/‐ mice. The mRNA levels of TLR2, TLR4, CBS, CSE, and SRB were measured by real‐time PCR. Free sulfide levels in colon and feces were determined by colorimetric assays. Results NaHS and GYY4137, donors of H2S, reduced the contractility of colon. Aminooxyacetic acid (AOAA), inhibitor of CBS, and D‐L propargylglycine (PAG), inhibitor of CSE, increased the contractility of colon. In vivo treatment with NaHS or GYY4137 inhibited the spontaneous contractions and upregulated TLR2 expression. The in vivo activation of TLR4 with lipopolysaccharide increased the contractile response to PAG, mRNA levels of CSE, and the free sulfide levels of H2S in colon. In Tlr2‐/‐ and Tlr4‐/‐ mice, the contractions induced by AOAA and PAG and mRNA levels of CBS and CSE were lower with respect to WT mice. Deficiency of TLR2 or TLR4 provokes alterations in free sulfide levels and SRB of colon. Conclusions and Inferences Our study demonstrates interaction between TLR2 and TLR4 and the sulfide system in the regulation of colonic motility and contributes to the pathophysiology knowledge of intestinal motility disorders.

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“…In response to proinflammatory cytokines, the leukocyte or macrophages are activated and recruited to the endothelium, thus causing the development of endothelial dysfunction-related cardiovascular diseases (Fang et al, 2013). Fortunately, H 2 S is found to alleviate vascular inflammation through various signaling pathways, including inhibition of NF-kB and nucleotide-binding oligomerization domain, leucine rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome, activation of KATP channels and voltage-and calcium-gated potassium (BKCa) channels (Fiorucci et al, 2005;Zanardo et al, 2006;Zuidema et al, 2010;Altaany et al, 2014;Bourque et al, 2018;Li et al, 2019). These possible mechanisms of H 2 S may explain that H 2 S can diminish vascular inflammation and attenuate the vascular injury, suggesting that the antiinflammation effect of H 2 S is a benefit for cardiovascular protection.…”

Section: Role Of H 2 S In Endothelial Inflammationmentioning

confidence: 99%

Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide

et al. 2020

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Endothelial cells are important constituents of blood vessels that play critical roles in cardiovascular homeostasis by regulating blood fluidity and fibrinolysis, vascular tone, angiogenesis, monocyte/leukocyte adhesion, and platelet aggregation. The normal vascular endothelium is taken as a gatekeeper of cardiovascular health, whereas abnormality of vascular endothelium is a major contributor to a plethora of cardiovascular ailments, such as atherosclerosis, aging, hypertension, obesity, and diabetes. Endothelial dysfunction is characterized by imbalanced vasodilation and vasoconstriction, elevated reactive oxygen species (ROS), and proinflammatory factors, as well as deficiency of nitric oxide (NO) bioavailability. The occurrence of endothelial dysfunction disrupts the endothelial barrier permeability that is a part of inflammatory response in the development of cardiovascular diseases. As such, abrogation of endothelial cell activation/inflammation is of clinical relevance. Recently, hydrogen sulfide (H 2 S), an entry as a gasotransmitter, exerts diverse biological effects through acting on various targeted signaling pathways. Within the cardiovascular system, the formation of H 2 S is detected in smooth muscle cells, vascular endothelial cells, and cardiomyocytes. Disrupted H 2 S bioavailability is postulated to be a new indicator for endothelial cell inflammation and its associated endothelial dysfunction. In this review, we will summarize recent advances about the roles of H 2 S in endothelial cell homeostasis, especially under pathological conditions, and discuss its putative therapeutic applications in endothelial inflammation-associated cardiovascular disorders.

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H2S protects lipopolysaccharide-induced inflammation by blocking NFκB transactivation in endothelial cells

Cited by 43 publications

References 45 publications

Hydrogen Sulfide Ameliorates High Glucose-induced Inflammation Through SIRT1-mTOR/NF-κB Signaling Pathway in HT-22 cells

Hydrogen Sulfide Ameliorates High Glucose-induced Inflammation Through SIRT1-mTOR/NF-κB Signaling Pathway in HT-22 cells

TLR2 and TLR4 interact with sulfide system in the modulation of mouse colonic motility

Role of Endothelial Dysfunction in Cardiovascular Diseases: The Link Between Inflammation and Hydrogen Sulfide

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